Systemic Levels of Estrogens and PGE2 Synthesis in Relation to Postmenopausal Breast Cancer Risk

Kim, Sangmi; Campbell, Jeff; Yoo, Wonsuk; Taylor, Jack A.; Sandler, Dale P.

doi:10.1158/1055-9965.epi-16-0556

Cited by 18 publications

(20 citation statements)

References 43 publications

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“…In the current study, which was smaller than the previous studies and cross-sectional rather than prospective, PGE-M was not significantly higher in cases than in controls. We did find that higher BMI was associated with higher PGE-M as determined by LC/MS but not by EIA (Morris et al , 2013; Cui et al , 2014), and we did not replicate a reported correlation between urine PGE-M and urine oestrone (E1) levels (Kim et al , 2017).…”

Section: Discussioncontrasting

confidence: 74%

“…Consistent with this, elevated C-reactive protein in serum has been associated with increased risk for postmenopausal breast cancer, at least among overweight and obese women (Hong et al , 2013; Gunter et al , 2015). Extending this theme, a potential marker of inflammation, PGE-M, was reported to be modestly elevated prior to postmenopausal breast cancer diagnosis in three previous studies (Kim et al , 2013, 2017; Cui et al , 2014). In the current study, which was smaller than the previous studies and cross-sectional rather than prospective, PGE-M was not significantly higher in cases than in controls.…”

Section: Discussionmentioning

confidence: 82%

“…Systemically, epidemiologic and clinical studies have found that inhibition of the COX2-PGE pathway through use of aspirin, and to a lesser extent, other nonsteroidal anti-inflammatory drugs is associated with a 10–20% reduced risk of oestrogen receptor (ER)-positive breast cancer incidence or recurrence (Gierach et al , 2008; Bardia et al , 2011; Silva et al , 2012; Bowers et al , 2014; de Pedro et al , 2015; Yiannakopoulou, 2015; Zhong et al , 2015). Notably, high urinary levels of the major prostaglandin E 2 metabolite (PGE-M) have been predictive of increased risk of breast cancer in three prospective studies of postmenopausal women, albeit with some inconsistencies (Kim et al , 2013, 2017; Cui et al , 2014).…”

mentioning

confidence: 99%

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Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

et al. 2018

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Section: Discussioncontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

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Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

et al. 2018

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“…The regulation of COX-2 by BPA might be related to the interaction of COX-2 and estrogen. In various estrogen-dependent tumors including endometrial cancer and ovarian cancer, estrogen promotes the proliferation and invasion of cancer by upregulating COX-2 expression 34,35 . COX-2 is involved in the positive feedback regulation between estrogen and inflammatory factors, where COX-2/ mPGES-1 upregulates the expression of aromatase and increases the levels of estrogen, which in turn upregulates COX-2 expression via combination with the estrogen receptor 36 .…”

Section: Discussionmentioning

confidence: 99%

The prostaglandin synthases, COX-2 and L-PGDS, mediate prostate hyperplasia induced by low-dose bisphenol A

Huang

et al. 2020

Sci Rep

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This study aimed to identify prostaglandin synthases (PGS) that mediate bisphenol A (BPA)-induced prostatic hyperplasia and explore their underlying mechanisms. In an in vivo study, male adult Sprague-Dawley rats were treated with different concentrations of BPA (10, 30, 90, or 270 μg/ kg, i.g., daily), or with vehicle for 4 weeks. Results revealed that low-dose BPA induced prostatic hyperplasia with increased PCNA/TUNEL ratio. It significantly upregulated the expression of cyclooxygenase-2 (COX-2) and NF-κB in the dorsolateral prostate (P < 0.05) and the expression of lipocalin-type prostaglandin D synthase (L-PGDS) in ventral prostate (P < 0.05). The level of estradiol (E 2)/testosterone (T) and expression of androgen receptor (AR) and estrogen receptor α (ERα) were also altered. In vitro studies showed that low-dose BPA (0.1-10 nM) promoted the proliferation of human prostate fibroblasts and epithelial cells, and significantly upregulated the expression of COX-2 and L-PGDS in the cells. The two types of cell proliferation induced by BPA were inhibited by COX-2 inhibitor (NS398) and L-PGDS inhibitor (AT56), with increased apoptosis level. These findings suggested that COX-2 and L-PGDS could mediate low-dose BPA-induced prostatic hyperplasia through pathways involved in cell proliferation and apoptosis, which might be related to the functions of ERα and AR. The role of COX-2/NF-κB pathway in dorsolateral prostate requires further research. Bisphenol A (BPA) is a synthetic plasticizer that is widely used to package daily necessities 1. Environmental exposure to BPA has potential toxicity to the tissues of male system including those of the testes and prostate 2 , leading to abnormal prostate development and a trend of hyperplasia 3. Prostate epithelial cells and prostate fibroblasts are the two main cell that constitute prostate tissues. Excessive proliferation of epithelial cells and prostate fibroblasts, and the transformation of epithelial cells to mesenchymal cells are involved in the pathogenesis of prostate hyperplasia 4,5. Low-dose BPA (0.01-1 nM) has been reported to promote the proliferation of primary prostate epithelial cells in rats 6. Similar to estradiol (E 2), BPA promotes the proliferation of human prostate epithelial stem cells and increases the possibility of human prostate epithelial carcinoma 7. However, the underlying mechanism of its effect on prostate cell proliferation and prostate hyperplasia remains unclear. As a typical environmental endocrine disruptor (EDC), BPA can disturb the endocrine functions by mimicking, enhancing, or inhibiting the endogenous estrogen activity, interfering with the androgen system 8 , and affecting the expressions of endocrine hormone-related genes and pathways. Prostaglandin synthases (PGS) catalyze the formation of different active prostaglandins (PGs) in the arachidonic acid metabolic pathway. There are four main PGS that are closely associated with hormonal function. Cyclooxygenase-2 (COX-2) is an inducible prostaglandin H synthase that is less expressed i...

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“…We were able to show that female MSC secrete signi cantly more PGE-2 in primed MSC-S than males. Research has indicated that sex hormones play roles in controlling the presence and function of PGE-2 and may work via a feedback loop in female adipose tissue [69,70], a possible mechanism responsible for the elevated PGE-2 response to in ammatory stimuli in fMSC and subsequent immune regulation.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell Mediated Immune Modulation Is Donor Sex Specific

Mckinnirey

Herbert

Vesey

et al. 2021

Preprint

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Mesenchymal stromal/stem cells (MSCs) are currently being used in clinical trials as proposed treatments for a large range of genetic, immunological, orthopaedic, cardiovascular, endocrine and neurological disorders. MSCs are potent anti-inflammatory mediators which are considered immune evasive and employ a large range of secreted vesicles to communicate and repair damaged tissue. Despite their prolific use in therapy, sex specific mechanism of action is rarely considered as a potential confounding factor for use.The purpose of this study was to examine the potency and functionality of both female and male adipose derived MSCs in order to gain further insights into donor selection. Using functional immune assays, ELISA, multiplex and immunophenotyping we showed female MSCs (fMSC), consistently suppressed Peripheral blood mononuclear cell (PBMC) proliferation significantly (p<0.0001) more than male MSC (mMSC). In co-culture mPBMCs, showed 60.7+/-15.6% suppression with fMSCs compared with 22.5+/-13.6% suppression with mMSCs. Similarly, fPBMCs were suppressed by 67.9+/-10.4% with fMSCs compared to 29.4+/-9.3% with mMSCs. The enhanced immunosuppression of fMSCs was attributed to the production of higher concentrations of the anti-inflammatory IL-1RA (1025 pg/ml vs 701 pg/ml), PGE-2 (6142pg/ml vs 2448 pg/ml), IDO (3301pg/ml vs 1699pg/ml) and prolonged expression of VCAM-1 post activation relative to mMSCs. In contrast, mMSCs produces more inflammatory G-CSF than fMSCs (806pg/mL vs 503 pg/mL). Moreover, fMSCs, but not mMSCs induced downregulation of the IL-2 receptor and sustained expression of the early T cell activation marker, CD69 in PBMCs further highlighting the differences in immunomodulation potentials between the sexes. In conclusion, our data shows that female MSC are more potent in vitro than their male counterparts. The inability of male MSC to match female MSC driven immunomodulation and to use the inflammatory microenvironment to their advantage is evident and is likely a red flag when using allogeneic male MSC as a therapeutic for disease states.

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Systemic Levels of Estrogens and PGE2 Synthesis in Relation to Postmenopausal Breast Cancer Risk

Cited by 18 publications

References 43 publications

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota

The prostaglandin synthases, COX-2 and L-PGDS, mediate prostate hyperplasia induced by low-dose bisphenol A

Mesenchymal Stem Cell Mediated Immune Modulation Is Donor Sex Specific

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